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1
Pharmaceutical sciences
Novel Drug Delivery Systems II
Introduction ofMultiple Emulsions
Paper No. : 08 Novel Drug Delivery Systems II
Module No : 18 Introduction ofMultiple Emulsions
Development Team
Principal Investigator
Dr. Vijaya KhaderFormer Dean, Acharya N G Ranga Agricultural University
Paper Coordinator
Content Writer
Content Reviewer
Prof. Farhan J Ahmad Jamia Hamdard, New Delhi
Dr. SushamaTalegaonkarJamia
Hamdard, New Delhi
Dr. SushamaTalegaonkarJamia
Hamdard, New Delhi
Prof Gurpreet Kaur
Punjabi University, Patiala, Pun jb
Prof. Farhan J Ahmad Jamia Hamdard, New Delhi
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Pharmaceutical sciences
Novel Drug Delivery Systems II
Introduction ofMultiple Emulsions
Description of Module
Subject Name Pharmaceutical Sciences
Paper Name Novel Drug Delivery Systems II
Module Name/Title Introduction ofMultiple emulsions
Module Id
Pre-requisites
Objectives Basic Introduction to multiple Emulsion
Advantages and Disadvantages of Multiple Emulsions
Formulation Components
Keywords Emulsion, Multiple emulsion , micro and nanoemulsion Surface
active agents, HLB
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Pharmaceutical sciences
Novel Drug Delivery Systems II
Introduction ofMultiple Emulsions
1. INTRODUCTION
Emulsions are the dispersed systems containing undissolved or immiscible drug distributed
throughout a vehicle. It is almost universally accepted that the term emulsion should be
limited to liquid-in- liquid systems in which dispersed phase is liquid that is neither soluble
nor miscible with the liquid of the dispersing phase. The particles of the dispersed phase are
usually solid materials that are insoluble in the dispersion medium. Emulsification results in
the dispersion of liquid drug as fine droplets throughout the dispersing phase. Since
approximately 1978, an additional type of emulsion classified as multiple emulsion with the
characteristics of oil- in-water- in-oil or water- in-oil- in-water emulsions was introduced. Such
emulsions also can invert, however, during inversion they usually form simple emulsions.
“An emulsion is thermodynamically unstable two phase system consisting of
atleast two immiscible liquids, one of which is finely sub-divided and uniformly
distributed as droplets throughout the other. The system is stabilized by the presence of an
emulsifying agent. The dispersed liquid or internal phase usually consists of globules of
diameters 0.1 to 10µm, although particle diameters as small as 0.01µm and as large as 100µm
are not uncommon in some preparations”.
2. TYPES OF EMULSION
i. Simple emulsions
a) Oil- in-water (O/W) Type: If the oil droplets are dispersed throughout the aqueous
phase the emulsion is termed as oil- in-water (o/w) type emulsion.
b) Water- in-oil (W/O): A system in which the water is dispersed throughout the oil is a
water-in-oil (w/o) emulsion.
ii. Multiple emulsions: Many small water droplets can be enclosed within larger oil
droplets, which are themselves then dispersed in water. This gives a water- in-oil- in-
water (w/o/w) emulsion. The alternative o/w/o emulsion is also possible.
iii. Micro emulsions: If the dispersed globules are of colloidal dimensions (1nm to 1µm
diameter) the preparation which is quite often transparent or translucent is called a
Microemulsion.
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Pharmaceutical sciences
Novel Drug Delivery Systems II
Introduction ofMultiple Emulsions
iv. Nanoemulsions:Nanoemulsion is considered to be a thermodynamically or kinetically
stable liquid dispersion of an oil phase and a water phase, in combination with a
surfactant. The dispersed phase typically comprises small particles or droplets, with a
size range of 5 nm-200 nm, and has very low oil/water interfacial tension.
3. MULTIPLE EMULSIONS
There are different types of specialized emulsions such as Multiple emulsions,
Microemulsions and Nanoemulsions.
These are complex polydispersed system where both oil in water and water in oil emulsion
exists simultaneously. These are stabilized by hydrophobic and hydrophilic surfactants
respectively. Multiple emulsions are also called as “emulsions of emulsions”, “double or
triple emulsions” because this type of emulsion itself contains dispersed globules, which are
miscible with the continuous phase. Sometimes certain multiple emulsions also termed as
“liquid membrane system” because the two miscible phases are separated by an immiscible
phase (liquid membrane) which acts as a semipermeable film through which solute must
diffuse in order to traverse from one phase to another.
These complex emulsions are covered by the broader definition of emulsions given by
International Union of Pure and Applied Chemistry (IUPAC) which extends the classical
definition to include “liquid droplets and/or liquid crystals dispersed in a liquid”. Several
modifications can be made in the development of the liquid membrane system depending on
the purpose for which it has to be prepared. Various additives can also be used to control the
stability, permeation and selection of membrane. Multiple emulsion has shown promises in
several technologies particularly in several pharmaceuticals and in separation science.
Multiple emulsions are commonly of two types (fig 1)
i. Water-in-oil-in-water (W/O/W)
In W/O/W systems, an organic phase (hydrophobic) separates internal and external aqueous phases or in other words, oil droplets may besurrounded by an aqueous phase, which in turn
encloses one or several water droplets.
ii. Oil-in-water-in-oil (O/W/O)
In O/W/O systems an aqueous phase (hydrophilic) separates internal and external oil phase or
in other words, water droplets may besurrounded in oil phase, which in turn encloses one or
more oil droplets.
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Pharmaceutical sciences
Novel Drug Delivery Systems II
Introduction ofMultiple Emulsions
MULTIPLE EMULSIONS
water phase = oilphase
W/O/W SYSTEM O/W/O SYSTEM
HYDROPHOBIC SURFACTANT
HYDROPHILIC SURFACTANT
O/W/O
Fig.1 W/O/W and O/W/O type emulsions
Multiple emulsions are complex system which consist of both w/o and o/w at the same
time.There are potential matrices for the encapsulation of bioactive compounds and for the
controlled release compounds.W/O/W multiple emulsion are system where small water
droplets are surrounded by larger oil droplets and they are dispersed in continuous water
phase. Diameter of the droplets in a multiple emulsion is in the range of 0.5 to 3µm.Because
of presence of reservoir phase these can be used to prolong release of active ingredients.
Multiple emulsion w/o/w contain two emulsifiers:
Low HLB surfactant (Hydrophobic in nature), used in disperse phase.
High HLB surfactant (Hydrophilic in nature), used in continuous phase
The basic rationale for the use of W/O/W & O/W/O type multiple emulsions as a means of
prolonged delivery of drugs is that the drug present in the innermost phase is forced to
partition itself through different phases beforeits release at the absorption site. Thusthe drug
release from these systems is controlled by partition & diffusion coefficient of the drug & the
strength of the middle membrane phase, which is a multimolecular layer of oil, water &
emulsifier molecules at both the interfaces of multiple emulsion system.
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Pharmaceutical sciences
Novel Drug Delivery Systems II
Introduction ofMultiple Emulsions
4. ADVANTAGES AND DISADVANTAGES OF MULTIPLE EMULSION
Advantages:
i. Masking of unpleasant taste: Although liquid dosage forms may be ideal for small
children who are unable to swallow solid dosage forms, many drugs taste unlikable
when formulated into a solution. It is possible to attempt to mask any unpleasant tastes
by the addition of a flavouring agent, but this will not always be successful. Such drugs
can be incorporated in the dispersed phase so that the external phase keeps them from
directly contacting to taste buds and taste can be masked. Examples are laxatives,
phenolphthalein, vitamin A, Castor oil, Cod- liver oil, Chloroquine Phosphate etc.
ii. Improved bioavailability: Absorption of drugs has been found to be faster and better
when formulated as emulsions. Small particle size of the drug present in disperse
systems result in a large specific area this leads to higher rate of drug dissolution and
possibly a superior bioavailability. Bioavailability of lipophilic drugs which have high
first pass metabolism can be increased by protecting drugs from GIT enzymes by
formulating multiple emulsions and placing the drugs in internal phase of the emulsion.
Eg. Atorvastatin, Lamotragine etc.
iii. Sustained release medication: Water soluble antigenic materials are dispersed in
mineral oil and are given as intramuscular injections. These preparations act as depots in
the muscle and release antigen from the oil slowly, over a long period. For sustained
release medication multiple emulsions are formulated in which drug present in
innermost phases has to cross several phases before it is available for absorption for the
system.
iv. Biocompatability and Biodegradability.
Since in multiple emulsions components used to produce hydrophobic and hydrophilic
phases are biodegradabletherefore this system have remarkable degree of
biocompatability and biodegradability.
v. Versatile drug carrier:bothhyrophilic as well as hydrophobic drugs can be entrapped
within multiple emulsion.
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Novel Drug Delivery Systems II
Introduction ofMultiple Emulsions
vi. Protection from inactivation by endogenous factors.Emulsions provide protection to
drugsthat are susceptible to oxidation or hydrolysis.
vii. Nutritional supplement: Terminally ill-patients are given nutrients parenterally. Fats
are dissolved in the oil phase and water soluble nutrients are incorporated in the aqueous
phase. Essential nutrients like carbohydrates, fats and vitamins can all be emulsified and
can be administered to bed ridden patients as sterile intravenous emulsions.
viii. Diagnostic Purposes: Radio-opaque emulsion are used as diagnostic materials in X-ray
examination. Intravenous emulsions of contrast media have been developed to assist in
diagnosis.
ix. Topical use:multiple emulsions are used in topical delivery as semisolid vehicles for
theenhancement of enteric or dermal absorption. examples are cold cream, vanishing
cream, benzyl benzoates, lotions, liniments, etc..
x. Economical: Expensive solvents are required to dissolve the lipids(oil soluble drugs).
Such substances can be easily dispersed in a less expensive vehicle such as water.
Hence emulsions can be made available at cheaper cost.
Disadvantages:
i. The main problem associated with multiple emulsions is their thermodynamic instability and their complex structure, because of which they are unstable and the insoluble phase separates slowly. Condition of storage may adversely affect the
disperse systems leading to creaming and cracking which has severely limited their usefulness in the many applications of multiple emulsions, so there is a need to
formulate stable emulsions such as microemulsions and nanoemulsions.
ii. Partitioning effect of emulsifiers, Phase inversion, Coalescence, Swelling and
shrinking of the internal droplets affect stability by influencing osmotic gradient for the passage of water across the oily membrane
iii. Being liquid dosage forms, they are much more bulky than their comparable solid
dosage forms.These makes emulsion heavier and difficult to transport.
iv. These are packed in glass or plastic containers thus care should be taken in hand ling
and storage.
5. PHYSICAL PROPERTIES OF WELL FORMULATED MULTIPLE EMULSION
The product must remain sufficiently homogenous for at least the period between shaking the
container and removing the required amount.
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Pharmaceutical sciences
Novel Drug Delivery Systems II
Introduction ofMultiple Emulsions
i. The sediment or creaming produced on storage, if any, must be easily re-suspended by
moderate agitation of the container.
ii. The product may be required to be thickened in order to reduce the rate of settling of the
particles or the rate of creaming of oil globules. The resulting viscosity must not be so
high that removal of the product from the container and transfer to the site of
application are difficult.
iii. Any suspended particles should be small and uniformly sized in order to give a smooth,
elegant product, free from a gritty texture.
6. FORMULATION INGREDIENTS OF MULTIPLE EMULSION SYSTEM
i.Oils
Oils used in the preparation of pharmaceutical emulsion are of various chemical types,
including simple esters, fixed and volatile oils, hydrocarbons, and terpenoid derivatives. The
oil itself may be the medicament or it may function as a carrier for a drug, or even form part
of a mixed emulsifier system as in the case of some fixed oils that contain sufficient free
acids. Many oils, particularly those of vegetable origin, are liable to autooxidation with
subsequent rancidity, so it is frequently necessary to add an antioxidant and/or preservative to
inhibit this degradation process. Selection of oil phase can effect various emulsion parameters
like yield, release profile, particle size and emulsion stability. The mineral oils give much
higher yield than the vegetable oils.
Table 1. Types of oil
Types of oil Examples
Fixed oil Arachis oil BP, Cod liver oil BP, Castor oil
BP
Mineral oil Liquid Paraffin BP ,
Liquid petrolatum
Volatile oil Cinnomon oil BP, Peppermint oil BP
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Novel Drug Delivery Systems II
Introduction ofMultiple Emulsions
ii. Pharmaceutical Emulsifiers
Emulsifying agents are used both to promote emulsification at the time of manufacturing and
to impart stability during the shelf life that can vary from days for extemporaneously
prepared emulsions to months or years for commercial preparations. In practice, combination
of emulsifiers rather than single agent is used.
The optimum concentration of surfactant required to emulsify given oil is determined by the
use of hydrophilic- lipophilic balance (HLB) system. In a W/O/W emulsion, the optimal HLB value of primary surfactant is usually in the range of 2-7 while it is 6-16 for the secondary
surfactant. The concentration of the emulsifiers can also be varied. Too little emulsifier may result in unstable systems,whereas too much emulsifier may lead to toxiceffects and can even cause destabilization. Anexcess of lipophilic surfactant can cause theinversion of w/o/w
emulsion to simple o/wemulsion.It is beneficial to use hydrophobic emulsifier in excess i.e. about 10-30% w/w of oil phase or primary emulsion whereas hydrophilic emuls ifier is used
in low concentration i.e. about 0.5%-5% w/w of external phase.
Table 2. Classification of emulsifying agent
EMULSIFYING AGENTS
Synthetic surfactants Hydrocolloid
emulsifying agents
Finely
Divided
Solids
anionic cationic nonionic amphoteric natural Semi-
synthetic
Colloidal
clays
Bentonite,
veegum
(Soaps ,Sulphates,Sul
phonates (CH3(CH2)n
CH2SO3Na+)
Quaternary ammonium
compounds
Tweens. Spans,
Lanolin alcohols
and ethoxylated lanolin
alcohols
lecithin Plant
origin
Polysacch- arides
(acacia, tragacanth, agar,
pectin)
Methyl cellulose,
Carboxy-methyl
cellulose Metallic
hydroxides
magnesium and
aluminum hydroxides
animal
origin
Gelatin,LecithinCholesterol, Wool
fat
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Introduction ofMultiple Emulsions
iii. Preservatives
It is essential that emulsions formulated should resist microbial attack, as this not only can
affect the physicochemical properties of the formulation, causing color, odor, or pH changes
and even phase separation, but may also constitute a health hazard. The potential sources of
contamination can be from raw materials (especially if these are natural products), water,
manufacturing and packaging equipment. O/W/O emulsions are less susceptible to attack
than W/O/W emulsions because the external aqueous phase can produce ideal conditions for
the growth of bacteria and fungi.
There is no simple way of predicting the ideal preservation for particular emulsion. In
addition a wide spectrum of activity against bacteria, yeast, and molds, the preservative
should be free from toxic, irritant, or sensitizing activity. Some commonly used preservatives
in oral and topical preparations include phenoxyethanol, benzoic acid, parabenzoates, and
chlorocresols. Emulsions are heterogenous products, and the preservative partitions between
the oil and the aqueous phases. A sufficient aqueous concentration of the active (usually
unionized) form must be present to ensure proper preservation. Problems often arise because
many of the materials used in emulsion formulation, for example hydrocolloids or
polyoxyethylene surfactants, can interact with the preservatives, thus depleting their activity.
iv. Antioxidants
Antioxidants are added to many pharmaceutical preparations to prevent oxidatitive
deterioration on storage of the oil, emulsifier, or the drug itself. Such deterioration, as well as
destabilization of the formulation, imparts an unpleasant odour or taste. Some oils are
supplied containing antioxidatnts already. Those commonly used in pharmacy include
butylatedhydroxyanisole(BHA) and butylated hydroxyl toluene(BHT) at concentration upto
0.2%, and the alkyl gallates, Propyl, octyl and dodecyl esters of gallic acid etc.
v. Other formulation additives:
a) Density modifiers; eg. Dextrose, sucrose, propylene glycol, glycerol, etc.
b) Humectants; eg. Glycerol, PEG, propylene glycol,etc.
c) Flavours, colours and perfumes; eg. Fruit juices, aromatic oils (peppermint, lemon),
carotenoids, anthocyanin, amaranth, etc.
d) Sweetening agents; eg.sucrose sorbitol, mannitol, aspartame etc.
e) Cosurfactants;eg. Glycerin, Ethylene glycol, Propylene glycol, Ethanol, Propanol,
Transcutol
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Novel Drug Delivery Systems II
Introduction ofMultiple Emulsions
7. FACTORS TO BE CONSIDERED BEFORE PREPARING MULTIPLE EMULSIONS
i) Hydrophilic-lipophilic balance (HLB)
The HLB number is an index describing the hydrophilic- lipophilic balance.A hydrophilic
emulsifier possess an high HLB number these are O/W emulsifiers.eg; Tween80(HLB 15),
Sodium oleate(HLB 18). On the other hand a lipophilic emulsifier has a low HLB number &
belongs to the W/O emulsifier group. Eg. Span80 (HLB 4.3)
GRIFFIN SCALE: Used For measurement of HLB of surfactants
SOLUBILISING AGENTS (16-20)
DETERGENTS(13-16)
O/W EMULSIFYING AGENTS (9-16)
WETTING & SPREADING AGENTS(7-9)
W/O EMULSIFYING AGENTS(4-8)
ANTIFOAMING AGENTS(1-3)
Fig.2 HLB Scale
HLB methods for selection of emulsifying agents
This method has been devised for calculating the relative quantities of the emulgents necessary to
produce the most physically stable emulsion for a particular oil/water combination. This is called the
hydrophilic- lipophilic balance (HLB) method.
for two surfactant mixture,
18
15
12
9
6
3
0
HLB blend = f x HLB (A) + (1-f) x HLB (B)
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Introduction ofMultiple Emulsions
f = fraction of surfactant (A) in the blend
For simple alkyl ethers in which the hydrophile consists only of ethylene oxide,
E = weight percentage of ethylene oxide groups
The HLB of polyhydric alcohol fatty acid esters such as glycerylmonostearate may be obtained
from the equation:
whereS is the saponification number of the ester and A is the acid number of the fatty acid.
HLB values can also be calculated from group contributions using:
ii) Bancroft’s rule:Bancroft’s rule describes the relationship between the nature of
emulsifying agent and type of emulsion formed. Though emulsifying agents have affinity
towards polar and nonpolar liquids they have preferential solubility in one of the liquids.
The phase in which an emulsifier is more soluble constitutes the continuous phase-
In O/W emulsions – emulsifying agents are more soluble in water than in oil (High HLB
surfactants).
In W/O emulsions – emulsifying agents are more soluble in oil than in water (Low HLB
surfactants).
Based on the Bancroft’s rule, it is possible to change an emulsion from O/W type to W/O
type by inducing changes in surfactant HLB.
HLB = E/5
HLB = ∑(hydrophilic group numbers) – ∑(lipophilic group numbers)+7
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Novel Drug Delivery Systems II
Introduction ofMultiple Emulsions
iii) Energy barrier and zeta potential
DLVO THEORY(Derjaguin Landau VerweyOverbeek Theory)
FIGURE-8 The two potentials involved in the DLVO theory are from an overlap of the
electric double layer(top line) and from the Vander Waals interaction(lower line). A sufficient
positive value of the total interaction(continuous line) gives particle stability.
Electric double layer: An ionic surfactant adsorb at the interface by orienting their
hydrophilic and hydrophobic parts towards polar and nonpolar phases of emulsion but some
counterions of the surfactant(eg. Sodium ion from sodium dodecyl sulfate) will separate from
the surface and form diffuse cloud reaching out in the continuous phase. Charged droplet
surface shows a diffuse layer of counterions. The surface and the co unterions called electric
double layer. When two droplets approach electrical double layer overlap, electric potential
between droplets increased which means that increased energy must be added with reduced
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Pharmaceutical sciences
Novel Drug Delivery Systems II
Introduction ofMultiple Emulsions
distance between droplets. An increase in energy means a repulsive force between droplets.
Since droplets are different from continuous medium a vanderwaals attraction potential is
also developed. The interaction between droplets is decided by total potential. On the other
hand, for small distances the resulting force is always negative and the particles will
spontaneously move towards each other.
The zeta potential is the electric potential in the interfacial double layer (DL). It is the
potential difference between the dispersion medium and the stationary layer of fluid remain
in touchwith the dispersed globules. The zeta potential is a key indicator of the stability of
multiple emulsions. The magnitude of the zeta potential indicates the degree of electrostatic
repulsion between similarly charged globules in a dispersion. For molecules and particles that
are small enough, a high zeta potential will impart stabilityby resisting aggregation in the
dispersion. When the potential is small, attractive forces may surpass this repulsion and the
dispersion may break. So emulsions with high zeta potential (negative or positive) are
electrically stabilized while with low zeta potentials tend to coalesce or aggregate.
Conclusion
The development and production of excellent pharmaceutical emulsions depends on the basic
knowledge of physicochemical properties and stability. Emulsifying agents play important
role in manufacturing of emulsions as they stabilize emulsion by preventing coalescence of
dispersed globules. They act as a bridge between the polar and nonpolar phases and reduce
the interfacial tension so its nature and concentration is important factor.Simple emulsion has
been advanced to multiple emulsion which is novel formulation for thebetterment of the drug
administration &improvement in the palatability of the drug.by incorporating them into the
variousformulations. Till date multiple emulsions have been shown to be able to protect labile
drug, delivering the unstable drug ,prevention of the drug from theenvironment, for
theimprovement of the various characteristicsof the drugslike taste masking,control drug
release, increase drug solubility, increase bioavailability and reduce patient variability.
Furthermore, it has proven possible to formulate preparations suitable for most routes of
administration.